Ornithine is metabolically degraded via three pathways. Ornithine is the substrate for the enzyme ornithine decarboxylase (ODC). ODC action on ornithine results in putrescine required for cell growth and division. From a quantitative point of view this pathway is normally quite insignificant but is important in rapidly dividing cells such as tumor cells.
Ornithine is also a substrate for L-Ornithine:2-oxoacid aminotransferase (OAT), a mitochondrial enzyme present in many tissues including liver, kidney, and brain. It catalyzes the transamination of L-ornithine (Orn) to 2-oxoglutarate, producing glutamic .gamma.-semialdehyde and glutamate. The liver enzyme is believed to function in the intracellular production of proline and the shuttling of carbon skeletons from excess dietary amino acids to the tricarboxylic acid cycle and it has been suggested that OAT competes with ornithine transcarbamylase for Orn and thus limits urea cycle activity. Inhibition of this enzyme can result in an excess of ornithine.
Ornithine is also the substrate for ornithine carbamoyltransferase (OCT), an enzyme of the urea cycle responsible for the conversion of ornithine to citrulline.
While ornithine is not normally considered an essential amino acid, certain conditions can arise naturally or can result from therapeutic intervention which produce a relative conditional efficiency of ornithine, for example, hepatic toxicity or failure, gastrointestinal hemorrhage, inherited urea cycle disorders, pregnancy, and malnutrition. In these instances, ornithine is rate limiting for urea cycle function. Administration of ornithine is largely ineffective because of the action of OAT, but inhibition of this enzyme would result in additional amounts of ornithine available for urea cycle function.
Various inhibitors of OAT are known. L-Canaline (2-amino-4-aminooxybutyric acid), for example, a naturally occurring structural analogue of Orn, forms an oxime with pyridoxalphosphate and affects a series of pyridoxalphosphate dependent enzymes. Because of this oxime formation, the biochemical effects of L-canaline can not be convincingly attributed to the inhibition of OAT.
Because of the structural analogy between Orn and 4-aminobutyric acid (GABA), and the analogous reaction mechanisms of OAT and 4-aminobutyric acid:2-oxoacid aminotansferase (GABA-T), some enzyme-activated irreversible inhibitors of GABA-T, such as 4-aminohex-5-ynoic acid and 5-amino-1,3-cyclohexadienylcarboxylic acid (gabaculine), are also potent irreversible inhibitors of OAT, but, by definition, are not specific for this enzyme.
The 5-substituted ornithine derivatives of this invention are the first known specific irreversible inhibitors of L-ornithine:2-oxoacid aminotransferase (OAT). When administered, the ornithine derivatives of this invention inhibit the transformation of L-ornithine to glutamic acid semialdehyde and thus cause an increase in ornithine concentration which would then be available to enhance urea cycle function in liver. As such, the compounds of this invention are useful in the treatment of conditional deficiencies of ornithine.